Synthetic glucocorticoids remain among the most effective agents for the treatment of chronic inflammatory diseases. However, major side effects severely limit their therapeutic use. Physiologic and therapeutic activities of glucocorticoids are mediated by a nuclear receptor belonging to a family of ligand-inducible transcription factors that, in addition to directly regulating their cognate gene programs, can also interfere with other signalling pathways, such as those using NF-κB.
NF-κB is an inducible transcription factor complex which regulates the expression of various genes involved in inflammatory and immune responses. It is activated upon exposure of cells to, among others, pro-inflammatory cytokines (such as TNF or IL-1), oxidants (such as hydrogen peroxide, ozone, superoxide anions), bacterial compounds, viral products, PKC activators (such as phorbol esters and platelet activating factor) and UV- or gamma-irradiation. NF-κB is therefore a promising target for anti-inflammatory and immuno-suppressive therapies. Inhibition of NF-κB activity by glucocorticoids has been well documented, although gene stimulatory effects by glucocorticoids have also been observed. Although glucocorticoids remain among the most potent immuno-suppressive and anti-inflammatory drugs currently available, and are especially effective in the treatment of chronic asthma or rheumatoid arthritis, side effects such as hypothalamic-pituitary-adrenal axis insufficiency, diabetes, altered lipid metabolism, steroid myopathy, osteoporosis, and infectious or neuro-psychiatric complications significantly limit the therapeutic use of classical glucocorticoid agonists in a significant number of patients, especially patients having a predisposition to one or more of the above-stated disorders.
WO01/45693 discloses 2-(4-acetoxyphenyl)-2-chloro-N-methylethyl-ammonium chloride as an anti-inflammatory agent.
Therefore there is a regular need in the art for novel compounds having significant and specific anti-inflammatory properties without having the side-effects of known effective anti-inflammatory agents such as glucocorticoids. There is a regular need in the art for effective anti-inflammatory agents having improved metabolisation and/or pharmacokinetic behaviour and which therefore can be more easily formulated into effective dosage forms. There is also a need in the art for such novel compounds which can be easily produced in good yield and purity from commercially available materials through a limited number of fully reproducible synthetic process steps.
Disorders in which cells are uncontrollably proliferating are generally referred to as cancer. This kind of disorders is commonly considered to result from a deregulation of the process that control cell division, differentiation and apoptosis. A combination of surgery, radiotherapy and chemotherapy is usually used for the treatment of Cancer. Chemotherapy is the treatment of cancer with drugs to kill cancer cells. Cytotoxic drugs usually used in chemotherapy are harming healthy tissue as well, and lead to a large variety of side effects.
Already two decades ago, natural and synthetic glucocorticoids have been identified as potential antitumor molecules in malignant melanoma, as inhibition of melanoma cell growth was observed, coinciding with reduced tumor size and weight. Glucocorticoid treatment of cancer, using Glucocorticoid Receptor (GR) agonists such as dexamethasone, aims at inducing apoptosis of cancerous cells. The GR-induced apoptotic effect has been described to require transactivation activity of that same receptor, therefore requiring a full GR agonist. E.g. systemic or local administration of dexamethasone significantly inhibits volume of brain tumors and reduces brain oedema (the latter remains a substantial cause of mortality). There is also some evidence in literature that glucocorticoids may target cancer by mediating effects in vascular functioning and angiogenesis. Various studies indicate that cytotoxic and cytostatic actions of glucocorticoids depend on GR transactivation activity that depends on GR dimerization (Sharma and Lichtenstein (2008) Blood, In Press)
Due to their high proliferation rate, cancer cells are prone to become resistant to chemical drugs. This is the case, for example, of prolonged glucocorticoid therapy, which presents the drawback that glucocorticoids induce down-regulation of their own cognate glucocorticoid receptors, which leads to therapy resistance.
Also, the success of classical glucocorticoid therapy for leukemia is overshadowed by potentially disabling side effects including e.g. hyperglycemia and a vascular necrosis of bone, especially prominent in young and adolescent patients.
As an alternative to dexamethasone treatment of cancer, prednisone, a corticosteroid with improved benefit over side effect ratio, has been used in the treatment of cancer as well. However, in some cases of severe malignancies, the use of dexamethasone in combination with radiotherapy or chemotherapy is preferred and the side effects then have to be considered as ‘collateral damage’ as the decision lies between survival or death.
There is a regular need in the art for novel compounds acting as anti-cancer agents that can be used, alone or in combination with another form or therapeutic treatment, for treating various forms of cancer.